A process for the synthesis of 2,2'-dithiobis[n-butyl-benzamide] in aqueous phase with ethyl acetate as additive

Abstract

The present application relates to the technical field of organic synthesis, in particular to a method for synthesizing 2,2'-dithiodi[N-butyl-benzamide] in water phase with ethyl acetate as additive. Sodium iodide and hydroiodic acid are used as key additives to synthesize 2,2'-dithiodi[N-butyl-benzamide], which has certain safety hazards. In view of the above problems, the present application provides a method for synthesizing 2,2'-dithiodi[N-butyl-benzamide] in water phase with ethyl acetate as additive, which is to use 2-butyl-1,2-benzisothiazoline-3-ketone as starting reaction material, sodium sulfide as reducing agent, and ethyl acetate as key additive to synthesize 2,2'-dithiodi[N-butyl-benzamide] in water under room temperature and closed condition. The method of the present application completely avoids the use of strong acid such as hydroiodic acid and sodium iodide. Moreover, the raw materials used are all conventional chemicals, the reaction system is mild, the operation process is safe and reliable, and it is suitable for large-scale production.

Description

Technical Field

[0001] This invention relates to the field of organic synthesis technology, and specifically to a method for synthesizing 2,2'-dithiodi[N-butylbenzamide] in an aqueous phase using ethyl acetate as an additive. Background Technology

[0002] Derivatives of 2,2'-dithiobis[N-butylbenzamide] have previously been shown to be relatively non-toxic platelet aggregation inhibitors, while also exhibiting strong bactericidal activity against common clinical microorganisms such as Staphylococcus aureus, Bacillus subtilis, and mycobacteria. In recent years, researchers have begun to explore the application potential of these compounds in the field of anti-mycobacterial activity. Preliminary experimental results show that these derivatives can not only inhibit the growth of Mycobacterium tuberculosis but also show some activity against some drug-resistant strains.

[0003] In previous studies, our research group reported a synthetic method for 2,2'-dithiodi[N-butylbenzamide]. This method uses sodium iodide and hydroiodic acid as key additives, and the target product is obtained through a ring-opening reaction at 100 degrees Celsius. However, this synthetic route has significant drawbacks: hydroiodic acid is a strong acid with strong corrosiveness, reducing properties, and irritant effects; iodides may release iodine vapor at high temperatures, posing safety and environmental risks.

[0004] Based on the above problems, developing a mild, environmentally friendly, and simple synthetic method is of great practical significance. To this end, this application proposes a green synthetic route that uses 2-butyl-1,2-benzisothiazolin-3-one and sodium sulfide as raw materials, and reacts in water at room temperature in a single step to efficiently prepare 2,2'-dithiodi[N-butyl-benzamide]. Summary of the Invention

[0005] The existing technology has the problem that using sodium iodide and hydroiodic acid as key additives to synthesize 2,2'-dithiodi[N-butyl-benzamide] poses certain safety risks. To address this problem, this invention provides a method for synthesizing 2,2'-dithiodi[N-butyl-benzamide] in an aqueous phase using ethyl acetate as an additive. The method involves reacting 2-butyl-1,2-benzisothiazolin-3-one as the starting material, sodium sulfide as the reducing agent, and ethyl acetate as the key additive in water under stirred conditions at room temperature and in a sealed environment to synthesize 2,2'-dithiodi[N-butyl-benzamide]. After the reaction is complete, the target product is obtained by separation and purification.

[0006] Preferably, during the reaction, the volume ratio of ethyl acetate to water is (1-9):(1-9).

[0007] Preferably, the volume ratio of ethyl acetate to water during the reaction is 1:9.

[0008] Preferably, during the reaction, the molar ratio of 2-butyl-1,2-benzisothiazolin-3-one to sodium sulfide is 0.2:(0.3-0.4).

[0009] Preferably, during the reaction, the molar ratio of 2-butyl-1,2-benzisothiazolin-3-one to sodium sulfide is 0.2:0.3.

[0010] Preferably, separation and purification refers to the reaction solution being sequentially subjected to extraction, heating and concentration, and silica gel column chromatography (silica gel particle size of 200-300 mesh) for separation.

[0011] Preferably, the extractant is ethyl acetate or dichloromethane.

[0012] Preferably, the eluent used in column chromatography is a mixture of ethyl acetate and petroleum ether in a volume ratio of 1:2.

[0013] Preferably, the mixture is concentrated by heating 25-30 times.

[0014] Beneficial effects: (1) This invention uses sodium sulfide as a reducing agent and ethyl acetate as an additive, completely avoiding the use of strong acids such as hydroiodic acid and sodium iodide. Hydroiodic acid is highly corrosive and irritating, and iodides easily release toxic iodine vapors at high temperatures, posing a significant safety hazard. The raw materials used in this invention are all conventional chemicals, the reaction system is mild, the operation process is safe and reliable, and it is suitable for large-scale production.

[0015] (2) Existing methods require heating the reaction at 100°C, while the present invention can be successfully completed at room temperature. No heating or cooling is required, which greatly reduces energy consumption and avoids the potential risks to equipment and operators caused by high temperatures.

[0016] (3) This invention uses a "one-pot" reaction, where the raw materials are added and stirred at room temperature, requiring no complex equipment. After the reaction is complete, the pure product can be obtained by extraction, concentration, and conventional silica gel column chromatography. The separation steps are mature and easy to operate. Detailed Implementation

[0017] The present invention will be described in detail below with reference to embodiments. However, it should be understood that the following embodiments are merely illustrative examples of implementation of the present invention and are not intended to limit the scope of the present invention.

[0018] Example 1 A method for synthesizing 2,2'-dithiobis[N-butyl-benzamide] is as follows: In a 25 mL sealed tube, 2-butyl-1,2-benzisothiazolin-3-one (0.2 mmol, 41.5 mg), sodium sulfide (0.3 mmol, 23.4 mg), and a mixture of ethyl acetate and deionized water (2.0 mL, ethyl acetate to deionized water volume ratio 9:1) were added sequentially. The mixture was stirred under sealed conditions at room temperature for 1 hour. After the reaction was complete, the reaction solution was extracted, concentrated (30 times), and separated by silica gel (200 mesh) column chromatography (eluent was a mixture of ethyl acetate and petroleum ether in a volume ratio of 1:2) to obtain the target product 2,2'-dithiodi[N-butyl-benzamide], with a yield of 90%. The reaction process is as follows: .

[0019] The NMR data of the obtained 2,2'-dithiobis[N-butyl-benzamide] are as follows: 1 H NMR (400 MHz, CDCl3) δ 7.65 (d, J = 8.3 Hz, 2H), 7.40 - 7.38 (m,2H), 7.25 (t, J = 7.7 Hz, 2H), 7.12 - 7.11 (t, J = 7.1 Hz, 2H), 6.22 (t, J =5.8 Hz, 2H), 3.34 (q, J = 6.9 Hz, 4H), 1.56 - 1.48 (m, 4H), 1.39 -1.29 (m,4H), 0.88 (t, J = 7.3 Hz, 6H).

[0020] 13 C NMR (75 MHz, CDCl3) δ 166.80, 135.70, 133.86, 129.99, 127.01, 126.39, 125.42, 38.86, 30.58, 19.16, 12.77.

[0021] Screening of key additive types Comparative Example 1 was the same as Example 1, except that 1,2-dichloroethane was used instead of ethyl acetate in Example 1. After the reaction, the yield of 2,2'-dithiobis[N-butylbenzamide] was 47%.

[0022] Comparative Example 2 was the same as Example 1, except that acetonitrile was used instead of ethyl acetate in Example 1. After the reaction, the yield of 2,2'-dithiobis[N-butylbenzamide] was 45%.

[0023] Comparative Example 3 was the same as Example 1, except that N,N-dimethylformamide was used instead of ethyl acetate in Example 1. After the reaction, the yield of 2,2'-dithiobis[N-butylbenzamide] was 38%.

[0024] Comparative Example 4 was the same as Example 1, except that tetrahydrofuran was used instead of ethyl acetate in Example 1. After the reaction, the yield of 2,2'-dithiobis[N-butylbenzamide] was 35%.

[0025] Comparative Example 5 was the same as Example 1, except that anhydrous methanol was used instead of ethyl acetate in Example 1. After the reaction, the yield of 2,2'-dithiobis[N-butylbenzamide] was 33%.

[0026] Comparative Example 6 was the same as Example 1, except that dichloromethane was used instead of ethyl acetate in Example 1. After the reaction, the yield of 2,2'-dithiobis[N-butylbenzamide] was 21%.

[0027] Comparative Example 7 was the same as Example 1, except that toluene was used instead of ethyl acetate in Example 1. After the reaction, the yield of 2,2'-dithiobis[N-butylbenzamide] was 0%.

[0028] Comparative Example 8 was the same as Example 1, except that dimethyl sulfoxide was used instead of ethyl acetate in Example 1. After the reaction, the yield of 2,2'-dithiobis[N-butylbenzamide] was 0%.

[0029] Screening of volume ratio of ethyl acetate to deionized water Example 2 was the same as Example 1, except that the volume ratio of ethyl acetate to deionized water was 1:9. After the reaction, the yield of 2,2'-dithiobis[N-butylbenzamide] was 95%.

[0030] Example 3 was the same as Example 1, except that the volume ratio of ethyl acetate to deionized water was 1:1. After the reaction, the yield of 2,2'-dithiobis[N-butylbenzamide] was 90%.

[0031] Comparative Example 9 was the same as Example 1, except that no deionized water was added during the reaction of Comparative Example 9; only 2 mL of ethyl acetate was added. After the reaction, the yield of 2,2'-dithiobis[N-butylbenzamide] was 45%.

[0032] Comparative Example 10 was the same as Example 1, except that no ethyl acetate was added during the reaction; only 2 mL of deionized water was added. After the reaction, the yield of 2,2'-dithiobis[N-butylbenzamide] was 83%.

[0033] Screening of sodium sulfide dosage Example 4 was the same as Example 2, except that the amount of sodium sulfide used in Example 4 was 0.4 mmol. After the reaction was completed, the yield of 2,2'-dithiobis[N-butylbenzamide] was 92%.

[0034] Comparative Example 11 was the same as Example 2, except that the amount of sodium sulfide used in Comparative Example 11 was 0.2 mmol. After the reaction was completed, the yield of 2,2'-dithiobis[N-butylbenzamide] was 54%.

[0035] Based on the above-described preferred embodiments of the present invention, and through the foregoing description, those skilled in the art can make various changes and modifications without departing from the inventive concept. The technical scope of this invention is not limited to the contents of the specification, but must be determined according to the scope of the claims.

Claims

1. A method for synthesizing 2,2'-dithiobis[N-butyl-benzamide] in an aqueous phase using ethyl acetate as an additive, characterized in that, 2,2'-dithiodi[N-butylbenzamide] was synthesized by stirring in water with 2-butyl-1,2-benzisothiazolin-3-one as the starting material, sodium sulfide as the reducing agent, and ethyl acetate as the key additive under room temperature and closed conditions. After the reaction was completed, the target product was obtained by separation and purification.

2. The method for synthesizing 2,2'-dithiobis[N-butyl-benzamide] in an aqueous phase using ethyl acetate as an additive according to claim 1, characterized in that, During the reaction, the volume ratio of ethyl acetate to water is (1-9):(1-9).

3. The method for synthesizing 2,2'-dithiobis[N-butyl-benzamide] in an aqueous phase using ethyl acetate as an additive according to claim 2, characterized in that, During the reaction, the volume ratio of ethyl acetate to water was 1:

9.

4. The method for synthesizing 2,2'-dithiobis[N-butyl-benzamide] in an aqueous phase using ethyl acetate as an additive according to claim 1, characterized in that, During the reaction, the molar ratio of 2-butyl-1,2-benzisothiazolin-3-one to sodium sulfide is 0.2:(0.3-0.4).

5. The method for synthesizing 2,2'-dithiobis[N-butyl-benzamide] in an aqueous phase using ethyl acetate as an additive according to claim 4, characterized in that, During the reaction, the molar ratio of 2-butyl-1,2-benzisothiazolin-3-one to sodium sulfide was 0.2:0.

3.

6. The method for synthesizing 2,2'-dithiobis[N-butyl-benzamide] in an aqueous phase using ethyl acetate as an additive according to claim 1, characterized in that, Separation and purification refers to the reaction solution being sequentially processed by extraction, heating and concentration, and column chromatography separation.

7. The method for synthesizing 2,2'-dithiobis[N-butyl-benzamide] in an aqueous phase using ethyl acetate as an additive according to claim 6, characterized in that, The extractant is ethyl acetate or dichloromethane.

8. The method for synthesizing 2,2'-dithiobis[N-butyl-benzamide] in an aqueous phase using ethyl acetate as an additive according to claim 6, characterized in that, The eluent used in column chromatography is a mixture of ethyl acetate and petroleum ether.